The present invention relates to mevinolin derivatives, a process for their production, their use as a pharmaceutical and pharmaceutical preparations containing them. More particularly the present invention provides a compound of formula I 
wherein
each of a - - - b and xcex1 - - - xcex2 independently, is either a single bond or a double bond;
R1 is

wherein Ra is H; C1-6alkyl optionally substituted by OH or C1-4alkoxy; C2-6alkenyl; or aryl-C1-4alkyl;
R2 is OH; xe2x80x94Oxe2x80x94COxe2x80x94R5 wherein R5 is C1-8alkyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-4alkyl, aryl or aryl-C1-4alkyl; or xe2x80x94Oxe2x80x94R6 wherein R6 is the residue of an xcex1-amino-acid attached to O through its carbonyl residue or xe2x80x94CHR7xe2x80x94COR5 wherein R7 is H, C1-4alkyl, hetero C1-4alkyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-4alkyl, aryl or aryl-C1-4alkyl and R8 is OH, C1-4alkoxy or NR9R10 wherein each of R9 and R10 independently is H, C1alkyl or R9 and R10 form together with the nitrogen to which they are bound, a heteroaryl group;
R3 is a substituted lactam, piperidyl, linear amino alcohol or cyclic carbamate, or a residue of formula (i) 
wherein
R13 is OH; C1-6alkoxy; xe2x80x94Oxe2x80x94COxe2x80x94C1-6alkyl; or xe2x80x94Oxe2x80x94COxe2x80x94NHC1alkyl;
R14 is OH; C1-4alkoxy; C1-4alkyl; C1-4alkoxy-carbonyl-C1-4alkoxy; hydroxy-C1-5alkoxy; C1-4alkoxy-C1-5alkoxy; C1-4alkoxy-carbonyl-C1-4alkyl; or NR9aR10a-C1-5alkoxy wherein each of R9a and R10a independently has one of the significances given for R9 and R10;
R15 is H or C1-4alkyl; and
R16 is CONR17R18 wherein one of R17 and R18 is H and the other is C1-6alkyl, hydroxy-C1-6alkyl, C3-7cycloalkyl-C1-4alkyl or aryl-C1-4alkyl; or C1-6alkoxy-carbonyl; each of a - - - b and xcex1 - - - xcex2 being a single bond when each of R13 or R14 is OH; and
R4 is H or OR19 wherein R19 is C1-6alkyl, hydroxy-C1-6alkyl, C1-4alkoxy-C1-6alkyl, aryl-C1-4alkyl or C1-4alkoxycarbonyl-C1-4alkyl,
and wherever xe2x80x9carylxe2x80x9d appears as is or in the significances of xe2x80x9caryl-C1-4alkylxe2x80x9d in the above definition, it is xe2x80x9cphenylxe2x80x9d or xe2x80x9cnaphthylxe2x80x9d optionally substituted by halogen, OH, NR11R12, COOH, CF3, C1-4alkoxy, C1-4alkyl, hydroxy-C1-4alkyl, hydroxy-C1alkoxy, C1-4alkoxy-carbonyl, cyano or CONR11R12, each of R1, and R12 independently being H, C1-4alkyl, phenyl, naphthyl, phenyl-C1-4alkyl or naphthyl-C1-4alkyl or R11 and R12 together with the nitrogen to which they are bound forming heteroaryl; and wherever xe2x80x9cheteroarylxe2x80x9d appears, it is a 5- or 6-membered heterocyclic residue optionally fused to a benzene ring; in free form or in salt form.
Alkyl groups or alkyl moieties may be branched or straight chain. Cycloalkyl groups or moieties are preferably cyclopentyl or cyclohexyl. Heteroalkyl includes e.g. halogenated alkyl such as CF3. Polyhydroxy-C1-4alkyl may comprise up to 6 hydroxy groups.
Preferably the phenyl or naphthyl moiety in aryl or aryl-C1-4alkyl, when substituted, bears up to 3 substituents as disclosed above, more preferably selected from C1-4alkoxy, e.g. methoxy or ethoxy, hydroxy-C1-4alkoxy, hydroxy-C1-4alkyl and OH. When the phenyl moiety is disubstituted, the 2 substitutents are preferably in positions meta and para. Aryl-C1-4alkyl is preferably benzyl, phenethyl or naphthyl-CH2xe2x80x94, the phenyl or naphthyl moiety being optionally substituted as indicated above.
Examples of heteroaryl include pyrrolyl, imidazolyl, turyl, thienyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, pyridyl, indolyl or quinolyl. Heteroaryl as formed by R5 and R10 together with the nitrogen to which they are attached, may comprise a further heteroatom, e.g. O or N, and is preferably pyrrolidinyl, piperidyl, piperazinyl or morpholino. In heteroaryl-C1-4alkyl, the alkyl moiety preferably is C1 or C2alkyl.
The significances given above for xe2x80x9carylxe2x80x9d and xe2x80x9cheteroarylxe2x80x9d also applies to the radicals of formulae (a), (b), (c1) or (c2) hereinafter.
When R6 is the residue of an xcex1-amino acid, it may be the residue of a natural or unnatural xcex1-amino acid residue, e.g. Ala, Leu, Ile, Val, Pro, wherein the terminal amino group may be substituted or unsubstituted, e.g. by an amino protecting group.
When R3 is a substituted lactam residue, it is preferably a 6-membered ring wherein the nitrogen of the lactam may be substituted and/or comprising a further substituent on the ring, e.g. on the carbon atom opposite to the nitrogen. Preferably the lactam residue is disubstituted. A suitable example of a substituted lactam as R3 includes e.g. a radical of formula (a) 
wherein
R30 is C1-8alkyl; C3-7cycloalkyl; aryl; C3-7cycloalkyl-C1-4alkyl; aryl-C1-4alkyl; heteroaryl; or heteroaryl-C1-4alkyl;
R31 is OH; C1-4alkoxy; C1-4alkyl; C1-4alkoxy-carbonyl-C1-4alkoxy; hydroxy-C1-5alkoxy; C1-4alkoxy-C1-5alkoxy; C1-4alkoxy-carbonyl-C1-4alkyl; amino-C1-4alkoxy; HOOCxe2x80x94C1-4alkoxy; HOOCxe2x80x94C1-4alkyl; or NR9aR10a-C1-5alkoxy wherein each of R9a and R10a independently has one of the significances given for R9 and R10.
When R3 is a substituted piperidyl residue, the nitrogen of the piperidyl may be substituted and/or a further substituent may be present on the ring, e.g. on the carbon atom opposite to the nitrogen. Preferably the piperidyl residue is disubstituted. A suitable example of a substituted piperidyl residue includes e.g. a radical of formula (b) 
wherein
R40 has one of the significances given for R30; and
R41 has one of the significances given for R31 or is xe2x80x94Oxe2x80x94COxe2x80x94C1-8alkyl.
When R3 is a substituted amino alcohol residue, the amino group thereof may be monosubstituted, e.g. by a substituent such as aryl-C1-4alkyl or aryl-C1-4alkyl-carbonyl, and/or a further substituent may be present on the chain, e.g. on the carbon atom adjacent to the alcohol or amino group. Cyclisation of the substituted amino alcohol residue leads to a corresponding substituted cyclic carbamate. A suitable example of a substituted amino alcohol and of the corresponding substituted cyclic carbamate includes e.g. a radical of formula (c1) or (c2) 
wherein
either each of X and Y is H or X and Y form together 
each of R50, independently is H; C1-8alkyl; C3-7cycloalkyl; aryl; C3-7cycloalkyl-C1-4alkyl; aryl-C1-4alkyl; heteroaryl; heteroaryl-C1-4alkyl; C1-4alkylcarbonyl; aryl-carbonyl; heteroaryl-carbonyl; aryl-C1-4alkyl-carbonyl or heteroaryl-C1-4alkyl-carbonyl, and
each of R51, independently is H; C1-4alkyl; hydroxy-C1-4alkyl; amino-C1-4alkyl; C1-4alkoxy-C1-4alkyl; C1-4alkoxy-carbonyl-C1-4alkyl wherein C1-4alkoxy is optionally substituted by amino, C1-4alkyl-amino or di-(C1-4alkyl)amino; HOOCxe2x80x94C1-4alkyl; or R23R24Nxe2x80x94COxe2x80x94C1-4alkyl wherein R23 is H, C1-4alkyl, hydroxy-C1-4alkyl, polyhydroxy-C1-8alkyl, heteroaryl, heteroaryl-C1-4alkyl, amino-C1-4alkyl, C1-4alkylamino-C1-4alkyl, di-(C1-4alkyl)amino-C1-4alkyl or aryl-C1-4alkyl and R24 is H, C1-4alkyl or hydroxy-C1-4alkyl, at least one of R50 and R51 being other than H.
Preferred compounds of formula I are those wherein R3 is substituted lactam, substituted linear amino alcohol, substituted cyclic carbamate, preferably substituted lactam or substituted cyclic carbamate, e.g. as disclosed above, more preferably a radical of formula (a) or (c1) or (c2) wherein X and Y are xe2x80x94COxe2x80x94.
In the compounds of formula I, the following significances are preferred individually or in any sub-combination:
1. R1 is H or CH3, preferably CH3;
2. R2 is xe2x80x94Oxe2x80x94COxe2x80x94R5, preferably wherein R5 is C4alkyl, particularly xe2x80x94CH(CH3)xe2x80x94CH2xe2x80x94CH3, xe2x80x94CH(CH2xe2x80x94CH2xe2x80x94CH3)2, xe2x80x94CH(CH2xe2x80x94CH3)2, xe2x80x94C(CH3)2xe2x80x94CH2xe2x80x94CH3 xe2x80x94CH2xe2x80x94CH3)xe2x80x94CH2xe2x80x94CH2xe2x80x94CH3.
3. a - - - b is a double bond;
4. xcex1 - - - xcex2 is a double bond;
5. R4 is H;
6. R3 is a radical of formula (i);
7. R16 is COxe2x80x94NR17R18; preferably one of R17 and R18 is H;
8. Each of R13 and R1-4 is OH and each of a - - - b and xcex1 - - - xcex2 is a single bond;
9. Each of R13 and R1-4 is other than OH;
10. R3 is a radical of formula (a);
11. R30 in (a) is aryl-C1-4alkyl or heteroaryl-C1-4alkyl, preferably benzyl or naphthyl-methyl wherein the phenyl or naphthyl ring is optionally substituted by OH, C1-4alkoxy, hydroxy-C1-4alkoxy or hydroxy-C1-4alkyl, or morpholino, pyridyl, indolyl or quinolyl;
12. R31 in (a) is OH, C1-4alkoxy, hydroxy-C1-4alkoxy, C1-4alkoxy-carbonyl-C1-4alkoxy or HOOCxe2x80x94C1-4alkoxy;
13. R3 is a radical of formula (c1) or (c2) wherein X and Y form together xe2x80x94COxe2x80x94;
14. R50 in (c1) or (c2) wherein X and Y form together xe2x80x94COxe2x80x94, is aryl-C1-4alkyl or heteroaryl-C1-4alkyl, preferably benzyl or naphthyl-methyl wherein the phenyl or naphthyl ring is optionally substituted by OH, C1alkoxy, hydroxy-C1-4alkoxy or hydroxy-C1alkyl;
15. R51 in (c1) or (c2) wherein X and Y form together xe2x80x94COxe2x80x94, is hydroxy-C1-4alkyl; amino-C1-4alkyl; C1-4alkoxy-C1-4alkyl; C1-4alkoxycarbonyl-C1-4alkyl; HOOCxe2x80x94C1-4alkyl; or R23R24Nxe2x80x94COxe2x80x94C1-4alkyl.
Compounds of formula I may exist in free form or in salt form, e.g. as acid addition salts with e.g. organic or inorganic acids, for example, hydrochlorides, or salts when a COOH is present, as salts with bases e.g. alkali salts such as sodium or potassium, or substituted or unsubstituted ammonium salts.
It will be appreciated that the radicals of formulae (i), (a), (b), (c1) and (c2) may comprise at least one asymetric carbon atom, e.g. the carbon atom which bears R15 and R16, R31, R41 or R51, respectively, for example 
Where the stereochemistry of any part of a compound of the invention is not specified, it is to be understood that the present invention embraces individual enantiomers and their mixtures. Similar considerations apply in relation to starting materials exhibiting asymetric carbon atoms as mentioned above. Where compounds of the invention exist in isomeric form as aforementioned, individual isomers may be obtained in conventional manner, e.g. employing optically active starting materials or by separation of initially obtained mixtures, for example using conventional chromatographic techniques.
The present invention also includes a process for the production of a compound of formula I, comprising
a) for the production of a compound of formula I wherein R3 is a residue of formula (i) submitting mevinolin or compactin or the corresponding tetrahydro-mevinolin or -compactin to ring opening, e.g. by reaction with a corresponding amine, e.g. arylamine; or
b) for the production of a compound of formula I wherein 3 is a radical of formula (c1) wherein each of X and Y is H, submitting to reductive amination the carbonyl function in Rxe2x80x33 in a compound of formula IV 
wherein R1, R2, R4, a - - - b and xcex1 - - - xcex2 and R1 are as defined above, and Rxe2x80x33 is a radical of formula (c1A) 
wherein R51 is as defined above; or
c) for the production of a compound of formula I wherein R3 is a residue of formula (c2) wherein each of X and Y is H, submitting mevinolin or compactin wherein the lactone ring has been converted into a conjugated ad unsaturated lactone, to a 1 ,4-addition e.g. with an amine, e.g. veratrylamine, and concomitant ring opening with an alcohol, e.g. methanol; or
d) for the production of a compound of formula I wherein R3 is a residue of formula (c1) or (c2) wherein each of X and Y is xe2x80x94COxe2x80x94, submitting to cyclisation a compound of formula I wherein R3 is a residue of formula (c1) or (c2) wherein each of X and Y is H; or
e) for the production of a compound of formula I wherein R3 is a substituted lactam, e.g. a residue of formula (a), submitting a compound of formula I wherein R3 is a residue of formula (i) wherein R13 is OH oxidised to a ketone and R16 is CONHR18, to a reductive amination and concomitant ring closure; or converting the free OH group in R3 in a compound of formula I wherein R3 is a residue of formula (i) wherein R16 is CONHR18, into a leaving group, e.g. by mesylation, and then submitting the resulting compound to a basic treatment; or
f) for the production of a compound of formula I wherein R3 is a substituted piperidyl, e.g. a residue of formula (b), reducing a compound of formula I wherein R3 is a substituted lactam, e.g. a residue of formula (a);
and, where required, removing the protecting group where present, and converting the resulting compound of formula I in free form or in salt form.
Where OH groups are present in the starting products which are not to participate in the reaction, they may be protected, in accordance with known methods. OH protecting groups are known in the art, e.g. tert.-butyl-dimethyl-silanyl.
Process steps (a) to (f) may be effected analogously to methods known in the art or as disclosed in the Examples below. The cyclisation in step (d) may conveniently be carried out in the presence of a cyclisation agent, e.g. carbonyl diimidazole.
Compounds of formula IV may be prepared by opening of the OH protected lactone ring according to known procedures, e.g. by reaction with an amine and then oxidation of the resulting hydroxy group into a ketone. Insofar as the production of the starting materials is not particularly described, the compounds are known or may be prepared analogously t methods known in the art or as disclosed in WO 99/11258, e.g. starting from mevinolin or compactin or tetrahydro-mevinolin or -compactin. The xe2x80x94Oxe2x80x94COxe2x80x94CH(CH3)xe2x80x94C2H5 of mevinolin, compactin or tetrahydro-mevinolin or -compactin may also be reduced to OH and then esterified to another xe2x80x94Oxe2x80x94COxe2x80x94R5 group.
The following Examples are illustrative of the invention. Following abbreviations are used:
Boc=tert.-butoxy-carbonyl
rt=room temperature
OMe=methoxy
THF=tetrahydrofurane
DMF=dimethylformamide
DCC=N,Nxe2x80x2-dicyclohexylcarbodiimide
Pro=proline
TBDMS=tert-butyldimethylsilyl
DMAP=dimethylaminopyridine
CDI=carbonyldiimidazole
TBME=tert-butylmethylether
CHX=cydohexane